Macrophages function as an essential component of innate immune system, contributing to both the initiation and appropriate resolution of inflammation. The exposure of macrophages to the microbial products, such as lipopolysaccharide (LPS), can strongly shift the balance between tissue homeostasis a
nd inflammation in favor of causing systemic damage, in which macrophage M1 polarization play important roles. Strategies aiming at restoring the balance of macrophage polarization remain to be further explored. Herein, we have demonstrated that poliovirus receptor (PVR), the receptor of TIGIT, was dramatically upregulated on the surface of mouse peritoneal macrophages when exposed to LPS. TIGIT-Fc fusion protein not only inhibited the macrophage activation, but also skewed M1/M2 balance toward an anti-inflammatory profile, especially enhanced the secretion of IL-10. The activation of TIGIT/PVR pathway in macrophages correlated with increased nuclear translocation of c-Maf, which promotes IL-10 transcription. Treatment with fibroblasts stably secreting TIGIT-Fc fusion protein significantly reversed the lethal and sublethal endotoxic shock, which facilitated peritoneal macrophages to switch towards anti-inflammatory M2 cytokine profiles. These findings highlight a novel role of the TIGIT/PVR pathway in macrophage M2 polarization and suggest that TIGIT may have the potential to optimize the treatment of macrophage-involved inflammatory diseases.
Human T-cell leukemia virus type 1 (HTLV-1) infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL) in some infected individuals. The HTLV-1 bZIP factor (HBZ) gene, which is encoded in the minus strand of HTLV-1, plays critica
l roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT), in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg) mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT-CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT's ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1.
Zhang B, etal., Cancer Immunol Immunother. 2016 Mar;65(3):305-14. doi: 10.1007/s00262-016-1799-4. Epub 2016 Feb 3.
T cell Ig and ITIM domain (TIGIT) is a newly identified inhibitory receptor expressed on T and natural killer (NK) cells. Cytokine-induced killer (CIK) cells express CD3 and CD56 molecules, and share functional properties with both NK and T cells. However, it r
emains unknown whether TIGIT is expressed in CIK cells. Here, we show that TIGIT is expressed by CIK cells and interacts with CD155. By blocking TIGIT using an anti-TIGIT functional antibody, we demonstrate that CIK cells display increased proliferation; higher cytotoxic targeting of tumor cells expressing CD155; and higher expression of interferon-gamma (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). Furthermore, increases in IFN-gamma and cytotoxicity by blockade of TIGIT were reduced by blocking DNAX accessory molecule-1 (DNAM-1) signaling, implying that TIGIT exerts immunosuppressive effects by competing with DNAM-1 for the same ligand, CD155. Our results provide evidence that blockade of TIGIT may be a novel strategy to improve the cytotoxic activity of CIK cells.
HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infectio
n in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion.
Godefroy E, etal., Haematologica. 2015 Nov;100(11):1415-25. doi: 10.3324/haematol.2015.132738. Epub 2015 Aug 6.
T follicular helper cells are the main CD4(+) T cells specialized in supporting B-cell responses, but their role in driving transfusion-associated alloimmunization is not fully characterized. Reports of T follicular helper subsets displaying various markers and functional activities underscore the n
eed for better characterization/identification of markers with defined functions. Here we show that a previously unidentified subset of human circulating T follicular helper cells expressing TIGIT, the T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains, exhibit strong B-cell help functions. Compared to the subset lacking the receptor, T follicular helper cells expressing this receptor up-regulated co-stimulatory molecules and produced higher levels of interleukins (IL-21 and IL-4) critical for promoting B-cell activation/differentiation. Furthermore, this subset was more efficient at inducing the differentiation of B cells into plasmablasts and promoting immunoglobulin G production. Blocking antibodies abrogated the B-cell help properties of receptor-expressing T follicular helper cells, consistent with the key role of this molecule in T follicular helper-associated responses. Importantly, in chronically transfused patients with sickle cell anemia, we identified functional differences of this subset between alloimmunized and non-alloimmunized patients. Altogether, these studies suggest that expression of the T-cell immunoreceptor with Ig and immunoreceptor tyro-sine-based inhibitory domains not only represents a novel circulating T follicular helper biomarker, but is also functional and promotes strong B-cell help and ensuing immunoglobulin G production. These findings open the way to defining new diagnostic and therapeutic strategies in modulating humoral responses in alloimmunization, and possibly vaccination, autoimmunity and immune deficiencies.
